By Allyson Luong

The coronavirus disease 2019 (COVID-19) was first reported on December 2019 in Wuhan, China and has become a global pandemic due its worldwide spread. COVID-19 is mainly known for causing respiratory symptoms, however in severe cases, it may also cause neurological harm. Neurological manifestations of COVID-19 affect both the central nervous system (CNS) and the peripheral nervous system (PNS). One of the symptoms of the coronavirus in the CNS include epilepsy (Azhideh 2020). 

Epilepsy is a common neurological disorder that causes seizures when nerve cell activity in the brain is disturbed. The suggested mechanisms of this disorder are an abnormal increase in neuronal activity due to a decrease in the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) and an increase in the excitatory neurotransmitters glutamate and aspartate (Nikbakht 2020). Impaired regulation of the activation of inflammatory responses in the injured neuronal tissue is a critical factor to epilepsy development. However, how the unbalanced regulation of inflammation contributes to epilepsy is still relatively unknown. Therefore, one of the goals in epilepsy research is to identify the connection between an uncontrolled inflammatory response and the progression of epilepsy (Rana 2018). 

A possible way that COVID-19 increases the risk of epilepsy is the way the virus enters the CNS. Angiotensin-converting enzyme 2 (ACE2) are proteins found in epithelial cells which create a protective barrier by lining tissues and organs in the human body. ACE2 receptors provide an entry way for viruses to enter and infect human host cells (Nikbahkt 2020). When the coronavirus binds to ACE2 receptors in the spinal cord, this allows the virus to invade the CNS (Yavapour-Bali 2020). The virus travels through the CNS via anterograde transport, the outward movement from cell body to synapse. This viral invasion triggers the immune system to release inflammatory cytokines which cause chronic inflammation and increase neural excitability (Nikbakht 2020). Cytokines increase the activation of the excitatory neurotransmitter glutamate by increasing the calcium entry into neurons through glutamate receptors (Yavarpour-Bali 2020). Also known as the COVID-19 infection cytokine storm, neuroinflammation from rise of cytokine release combined with CNS infection can result in neuronal epilepsy (Nikbakht 2020). In sum, the entry and travel of COVID-19 in the CNS triggers an immune response that causes an increase in neural excitability and results in epilepsy. 

Another way COVID-19 can induce an increase of cytokine is by breaking down the permeability of the blood brain barrier (BBB) (Nikbaht 2020). The blood brain barrier serves as a semipermeable border that regulates what solutes and extracellular fluid can pass into the CNS. COVID-19 infection in the CNS causes a breakdown of the BBB permeability which disturbs the osmotic balance of the CNS and induces epilepsy (Nikbhakht 2020). Studies have shown that a higher seizure frequency was associated with a more permeable BBB (van Vliet 2006). Increased BBB permeability from the coronavirus infection allows cytokines another entry way into the CNS without the aid of ACE2 receptors. A weakened BBB disrupts the homeostasis of the brain and can lead to epilepsy development. 

A COVID-19 infection can also indirectly harm the CNS by causing oxidative stress on mitochondria. Oxidative stress has shown to be a result of COVID-19 which causes cytokines to increase reactive oxygen species (ROS) in mitochondria (Nickbakht 2020). At low levels, ROS help maintain mitochondrial homeostasis and metabolism but at high levels, ROS can lead to cell damage or even apoptosis (Zorov 2014). Mitochondria are organelles responsible for generating energy in the cells, which is vital for maintaining normal electrical activity in the transmission along neurons and synapses. Disruptions in mitochondrial function may lead to abnormal electrical activity of neurons and produce seizures (Nickbakht 2020). In other words, damage that causes mitonchondrial dysfunction increases ROS levels which disrupts the maintenance of electric activity among neuronal communication and contributes to the progression of epilepsy. Moreover, there seems to be a strong causal connection between mitochondrial dysfunction and the onset of seizures. 

Electrolyte homeostasis is another factor vital for proper brain function in the CNS. Regulation of ionic balance is a critical process responsible for the movement of ions entering and exiting the brain and for maintaining blood–brain barrier function as well as the mechanisms in the membranes of both neurons and glia cells. Disruptions in ion gradients across cellular membranes can have neuronal effects that may increase the risk of epilepsy (Castilla-Guerra, 2006). An infection from COVID-19 is associated with decreased serum concentrations of sodium, potassium, magnesium. Seizures are the most important clinical symptoms of electrolyte disturbances and are more common in patients with hyponatremia, hypocalcemia, and hypomagnesemia. (Nickbakht 2020). The effect of COVID-19 in disrupting the electrolyte homeostasis of sodium, potassium and magnesium may increase the likelihood of causing seizures; a common manifestation of patients with severely low levels of those three electrolytes. Studies show that acute and/or severe electrolyte imbalances frequently cause seizures (Castilla-Guerra, 2006). More importantly, successful management of patient seizures begins with establishing an accurate diagnosis of the underlying electrolyte disturbance. Changes in blood electrolytes may cause diffuse brain dysfunction and metabolic encephalopathy. Moreover, the major dangers from acute hyponatremia (severely low levels of sodium) are brain cell swelling and herniation (Castilla-Guerra, 2006). In other words, disrupting electrolyte diffusion can cause brain damage associated with brain swelling which is caused by an increased inflammatory response from the immune system. Similar to the other mechanisms in how COVID-19 increases the risk of epilepsy, disturbing electrolyte homeostasis is yet another method in how COVID-19 causes an unregulated increase of inflammation. Furthermore, understanding the causal relationship between COVID-19 and electrolyte disturbance may help create better treatments of patients that have seizures following a coronavirus infection. 

There are many different mechanisms in how an infection from COVID-19 may cause epilepsy. The common similarity among each mechanism stemmed from unregulated inflammatory responses through factors such as an increase of inflammatory cytokines in the CNS or increased neural-excitability. Although the long-term neurological impacts of COVID-19 require further research, understanding the underlying neuropathology of the virus is vital to developing effective treatments in helping recovering COVID-19 patients with epileptic symptoms.

References 

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